The ketone is one of the most important functional groups in organic chemistry, as it not only is widely found in natural/man-made products, but also is a versatile synthetic intermediate to other functionalities. Over the past several decades, progress has been made to achieve a ketone synthesis with high selectivity and efficiency. The Weinreb amide is recognized as the method of choice for monoaddition of an organometallic reagent, i.e., organolithium or Grignard reagent, and the reliability and effectiveness of Weinreb ketone synthesis have been demonstrated for a wide range of substrates (FIG. 9) (see, e.g., Nahm et al., Tetrahedron Lett. 1981, 22, 3815). However, there are limitations in functional group tolerance with an organolithium or Grignard reagent. In that respect, work has been done to prepare Grignard reagents under mild conditions (see, e.g., Krasovskiy et al., Angew. Chem., Int. Ed. 2004, 43, 3333). In contrast, a transition-metal-catalyzed ketone synthesis, represented by Fukuyama ketone synthesis, has advantages, because it does not require a strongly basic and nucleophilic reagent (FIG. 9) (see, e.g., Dieter, Tetrahedron 1999, 55, 4177, Fiandanese et al., Tetrahedron Lett. 1983, 24, 3677, Cardellicchio et al., Tetrahedron Lett. 1985, 26, 3595, Bagheri et al., Tetrahedron Lett. 1983, 24, 5181, Wittenberg et al., Org. Lett. 2003, 5, 3033, Liebeskind et al., J. Am. Chem. Soc. 2000, 122, 11260, Li et al., Org. Lett. 2011, 13, 3682, Zhang et al., J. Am. Chem. Soc. 2004, 126, 15964, Tokuyama et al., Tetrahedron Lett. 1998, 39, 3189, Miyazaki et al., Synlett 2004, 2004, 477, Fukuyama et al., Aldrichimica Acta 2004, 37, 87, and Cherney et al., Tetrahedron 2014, 70, 3259). The effectiveness of Fukuyama ketone synthesis has been demonstrated for a variety of substrates, even in an industrial scale (see, e.g., Shimizu et al., Tetrahedron Lett. 2001, 42, 429 and Mori et al., Adv. Synth. Catal. 2007, 349, 2027). However, this method has been used for relatively small nucleophiles (often excess equivalents), thereby hinting at a potential issue in its use at a late stage in a multistep synthesis of complex molecules. In addition, preparation of an organometallic reagent is often cumbersome for complex substrates and their stability might become problematic during preparation.
Halichondrins are polyether macrolides, originally isolated from the marine sponge Halichondria okadai (see, e.g., Uemura et al., J. Am. Chem. Soc. 1985, 107, 4796 and Hirata et al., Pure Appl. Chem. 1986, 58, 701). This class of natural products displays interesting structure diversities on the oxidation state at C12 and C13, cf., halichondrin A-C in FIG. 1. Halichondrin B was chosen as a synthetic target and experimental work began, leading to the first total synthesis of halichondrin B in 1992. On completion of the synthesis (see, e.g., Aicher et al., J. Am. Chem. Soc. 1992, 114, 3162 and Ueda et al., J. Am. Chem. Soc. 2014, 136, 5171), the antitumor activities of the totally synthetic halichondrins were tested, along with several synthetic intermediates. The experiments clearly demonstrated that the antitumor activities of halichondrin B resided in the right portion of the molecule, which served as the foundation for successful development of the antitumor drug Halaven (Eribulin) (see, e.g., Zheng et al., J. Bioorg. Med. Chem. Lett. 2004, 14, 5551, Yu et al., Anticancer Agents from Natural Products; CRC Press: 2005, p 241, Yu et al., Annu. Rep. Med. Chem.; John, E. M., Ed.; Academic Press: 2011, Vol. 46, p 227, and Austad et al., Synlett 2013, 24, 333). The structure of Eribulin is shown below.
